16alpha-fluoromethyl-21-fluoro and 21-desoxy compounds of the pregnane series



3,388,138 160: FLUOROMETHYL 21 FLUORO AND 21- DESUFY COMPOUNDS OF THE PREGNANE SERIE Philip F. Bea] Ill, and John E. Pike, Kalamazoo, Mich, assignors to The Upjohn Company, Kalamazoo, Mich, a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 1,454, Jan. 11, 1960. This application May 6, 1966, Ser. No. 548,656

8 Claims. (Ci. Mil-397.4)

This application is a eontinuatiomin-part of application Ser. No. 1,454, filed Jan. 11, 1960, now U.S. Patent No. 3,261,851.

This invention relates to certain novel and therapeutically useful steroids and more particularly to (A) 16afiuoromethylhydrocortisone, 16a fluoromethylcortisone, l6u-fluoromethyl 17u,2l dihydroxy 4 pregnene 3,20 dione, l-dehydro-l6a-fluoromethylhydrocortisone, l-dehydro-16a-fluoromethylcortisone, 16oz fiuoromethyl-lfla, ZI-dihydroxy-l,4-pregnadiene-3,20-dione, the Zea-methyl and 6a-methyl derivatives of these compounds and the 21- acylates thereof; (B) a-fluoro-l6u-fiuoromethylhydrocortisone, 6a-fluoro-l6u-fluoromethylcortisone, 6a-fluoro- 16a-fluoromethyl-17a,2l-dihydroxy 4 pregnene-3,20- dione, 1 dehydro-6a-fluoro-l6a-fiuoromethylhydrocortisone, l-dehydro 6oz fluoro-l6cx-fluoromethylcortisone, 6a-fluoro 16a fluoromethyl 17,2l dihydroxy-IA- pregnadiene-3,20-dione and the 21-acylates thereof; (C) 9a-halo-l6a-fluoromethylhydrocortisone, 9a halo-16afluoromethylcortisone, 1-dehydro-9whalo-16a-fluoromethylhydrocortisone, l-dehydro 9a h-alo-16a-fluoromethylcortisone, especially the 9a-fiuoro compounds, the 2mmethyl, 6oz-methyl and 60L-fiIlOf-O derivatives of these compounds and the 21-acylates thereof; (D) the 21-fiuoro and 21-desoxy compounds including the l7-acylates thereof which correspond otherwise to the compounds of Groups (A), (B) and (C), above, the 17,21-epoxy compounds corresponding otherwise to the compounds of groups (A), (B) and (C), above, to novel steroid intermediates and to processes for the production thereof. The novel compounds of this invention, listed above under (A), (B), (C) and (D), can :be represented by the following formulae:

and

wherein R is hydrogen or the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, R is hydrogen, fluorine, hydroxy or OAc in which Ac is the acyl radical defined as above, X is selected from the States Patent ice group consisting of the methylene radical CH the B- hydroxymethylene radical and the carbonyl radical C=O), Y is hydrogen or methyl, Y is hydrogen, methyl or fluorine, Z is hydrogen, fluorine, chlorine or bromine, and wherein when X is the methylene radical Z is limited to hydrogen. The above compounds are highly potent cortical hormones having anti-inflammatory, glucocorticoid, salt and water regulating, progestational, pituitary inhibiting and anti-anabolic activities with improved ratio of therapeutic activity to undesirable side-effects, e.g., gastrointestinal disturbances, edema, etc., known to exist with similar known physiologically active steroid compounds. Many of the higher molecular weight esters of the 2l-hydroxy compounds, particularly those resistant to hydrolysis and/ or more insoluble in body fluids, provide compounds having more prolonged activity than the corresponding 21-hydroxy compounds. The above-named compounds are particularly useful in the treatment of various inflammatory conditions of the skin, eyes, respiratory tract and the bones and internal organs, contact dermatitis and allergic reactions, rheumatoid arthritis, and possess improved therapeutic ratios of anti-inflammatory activity to undesirable sideetfects, compared to the corresponding compounds lacking the 16ot-fluoromethyl group.

The novel 17,2l-epoxy compounds of Group (D) of this invention represented by the following formulae:

@ij CHzF v fw Y 1/3 wherein X Y, Y and Z have the meanings previously given and wherein when X is methylene Z is hydrogen, possess particularly marked diuretic activity in that they cause a loss of salt and water which makes them especially valuable in the treatment of cirrhosis of the liver, the nephrotic syndrome, and the treatment of eclampsia and preeclampsia.

Other compounds of this invention, as well as being useful as intermediates in the production of the above described compounds, also possess useful physiological activities, including anti-inflammatory, glucocorticoid, salt and water regulating, progestational, anti-fertility, muscle relaxing, central nervous system depressant and cardiotonic activities. Among these are the compounds represented by Formulae II, III, IIIa, IV, V, Va, VI, VIa, VIb, IX, DCa, A-II, AIV, A-V, A-VI, A-VIII, A-IX, A -II, A -III and A IV of the flow sheets set forth below.

The novel compounds of this invention and the therapeutically active intermediates can be prepared and 'administered to mammals, birds, humans and animals in a wide variety of oral, parenteral or topical dosage forms singly, or in admixture with other coacting compounds. They can be associated with a carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powder, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixirs. Pharmaceutical compositions and mixtures for topical use can take the form ointments, lotions, jellies, creams, aqueous suspensions and the like.

The following starting materials for the processes of this invention are known in the art: 4,16-pregnadiene-3, 11,20-trione, 4,16-pregnadiene-3,20-dione, B-acetoxy-16- pregnenell,20-clione and l6a-cyano-3/3-hydroxy-5-pregnen-ZO-one. The other starting materials, i.e., L's-methyl- 4,l6-pregnadiene-3,l1,20-trione, 6u-methyl 4,16 pregnadiene-3,11,20-trione, Za-methyl 4,16 pregnadiene-3,20- dione and 6a-methyl-4,l6-pregnadiene-3,20-dione are prepared from Za-methyI-Il-ketoprogesterone, 6a-methyl-llketoprogesterone, 2a-methylprogesterone and 6ot-rnethylprogesterone, respectively, by catalytic reduction to produce the corresponding saturated A ring compounds which can be converted to the 2a-methyl and 6a-methyl starting materials listed above according to the procedures of US. Patent 2,794,814, as shown in Preparations 1-5 contained herein.

Group A.-The novel compounds of Group A of this invention are represented 'by the following formulae:

ROUTE 1 l a (IJHa (3 0 C=O ROUTE 3 CH3 1:0 'i ]--ON fllj coon 03 -CHaF GROUP A cm and trans GHzOAO wherein Y, X and R have the meanings previously given, Ac is the acyl radical of an organic carboxylic acid, pref erably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, R is a lower alkylene radical containing from 1 to 8 carbon atoms, inclusive, and from 2 to 3 carbon atoms in the chain connecting the oxygen atoms, e.g., ethylene, trimethylene, 2,2-dimethyltrimethylene, n-propyl-ethylene, 1,l,2,2-tetrarnethylethylene, etc., R is hydrogen or methyl, R is an organic radical, particularly a hydrocarbon radical containing from one to ten carbon atoms, inclusive, e.g., methyl, ethyl phenyl, tolyl, naphthyl, etc., R is a lower alkyl radical containing from 1 to 8 carbon atoms, inclusive, X is the methylene radical or the carbonyl radical and X is the methylene radical or the B-hydroxymethylene radical.

ROUTE 1 In carrying out the process of Route 1, 4,16-pregnadiene-3,l1,20-trione, 4,16-pregnadiene-3,20-dione or the 2mmethyl and Got-methyl analogues thereof (I) are ketalized at the 3-position according to the method of US. Patent 2,707,184 or 2,758,993 or with the acetal of a loweralkylene glycol, e.g., dioxolane, Z-methyl-Z-ethyldioxolane, in the presence of an acid catalyst, e.g., p-toluenesulfonic acid, concentrated sulfuric acid, boron trifluoride, etc., to produce the corresponding 3-cyclic ketal of the selected 4,16-pregnadiene (II). Ethylene glycol is the preferred ketalizing agent.

The B-ketalized 4,16-pregnadienes (II) thus produced are then treated with an alkali-metal cyanide, e.g., potascis and trans XIV CHzOH sium cyanide or sodium cyanide, in the presence of a suitable solvent such as dioxane, methanol, ethanol, propanol, mixtures of these solvents and the like to produce the corresponding B-ketalized 16a-cyano-4-pregnene (III), which can be hydrolyzed by methods known in the art, e.g., US. Patent 2,707,184 or 2,758,993 to produce the corresponding free 3-keto compound (Illa).

The 3-ketalized l6a-cyano-4-pregnenes (III) are then ketalized at the 20-position with a lower-alkylene ocor fi-glycol, e.g., ethylene glycol in the presence of an acid catalyst, e.g., p-toluenesulfonic acid, sulfuric acid, etc. to produce the corresponding 3,20-diketalized IGe-cyanm 4-pregnene (IV). Reaction solvents which may be suitably employed include hydrocarbon solvents, halogenated hydrocarbons, ethers, and the like, e.g., benzene, xylene, hexane, chloroform, diethyl ether, tetrahydrofuran, dioxane, etc., or an excess of alkylene glycol can be used.

The 3,20-diketalized ll6a-cyano-4-pregnenes (IV) thus obtained are then dissolved in an organic solvent, e.g., ethylene glycol, propylene glycol, dimethylsulfoxide, ethanol, tertiary amines such as pyridine and the like, and hydrolyzed with an aqueous base such as an aqueous alkali metal hydroxide solution, e.g., potassium hydroxide or sodium hydroxide, to give the corresponding 3,20- diketalized 16a-carboxy-4-pregnene (V), which can be esterified with ethereal diazomethane solution to produce the corresponding 16ot-carbomethoxy compound (V).

The 3,20-diketalized 16et-carboxy or 160L-CZ1TbOl'llC- thoXy-4-pregnenes represented by Formula V, e.g., 16acarboxy-4-pregnene-3,l1,20-trione 3,20-bis(alkylene ketal) or 16u-carboxy-4-pregnene-3,20-dione bis(alkylene ketal), the 2aand Got-methyl analogues thereof or the corresponding lfivt-carbomethoxy compounds, are then reduced with lithium aluminum hydride or other carboxyl reducing agent in an organic solvent or mixtures of organic solvents, e.g., ether, dioxane, tetrahydrofuran, benzene, toluene, and the like, to produce the corresponding 3,20- diketalized 16a-hydroxymethyl 4 pregnene (VI), e.g., 1 1,8 hydroxy-l6a-hydroxymethyll-pregnene-3,ZO-dione bis(alkylene ketal), 16a-hydroxymethyl-4-pregnene-3,20- dione bis(alkylene ketal) and the 2aand Got-methyl analogues thereof. The ll-keto group when present in the starting material of this step are simultaneously reduced to the llB-hydroxy group.

The 3,20-diketalized 1lfi-hydroxy-l6a-hydroxymethyl- 4-pregnene-3,20-diones (VI) can be esterified by known methods, e.g., with a carboxylic acid anhydride in pyridine, to produce the corresponding l6u-acyloxymethyl compounds which can then be oxidized at the ll-position by known methods, e.g., with chromium trioxide in pyridine, chromic acid or sodium dichromate, chromic anhydride and dilute sulfuric acid, N-haloimide or N-haloamide in pyridine and the like to give the corresponding 3,20- diketalized 16a-acyloxymethyl-4-pregnene-3,11,20-triones (VIa) which on hydrolysis with aqueous base, e.g., aqueous sodium hydroxide, is productive of the corresponding 3,20 diketalized 16a hydroxymethyl 4 pregnene 3,11,20-triones represented by Formula VIa.

The compounds of Formulae V, VI and VIa are useful anti-inflammatory, glucocorticoid, salt and water regulating, progestational, antifertility, central nervous system depressant and cardiotonic agents. These compounds can be hydrolyzed if desired by known methods for hydrolyzing cyclic ketal groups, e.g., with dilute aqueous acid in the same manner as described above for hydrolyzing the 3-ketals, e.g., dilute aqueous acid, to give the free 3,20- ketones represented by Formulae Va and VIb, which have physiological activities similar to those of the parent compounds (VI) and (VIa), above. 7

The 3,20-diketalized lou-hydroxymethyl 4 pregnenes (VI) and (Via) are then reacted with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride, to yield the corresponding organic sulfonate ester of the 16a-hydroxymethyl group (VII), e.g., the p-toluene sulfonate, which on fluorination by means of potassium fiuorosulfinate or an alkali metal fluoride, e.g., anhydrous potassium fluoride in the presence of a solvent, e.g., ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol, and the like, at a temperature range between 100 and 300 C. in an atmosphere of nitrogen gives the corresponding 3,20- diketalized l6a-iluoromethyl-4-pregnene (VIII).

The compounds of Formula VIII thus produced are then hydrolyzed by known methods for hydrolyzing cyclic ketal groups, e.g., dilute sulfuric acid, according to the method of US. Patents 2,707,184 or 2,758,993 for hydrolyzing 3-cyclic ketals, to give corresponding Ida-fluoromethyl-4-pregnenes (IX), i.e., 11B-hydroxy-l6a-fluoromethyl-4-pregnene-3,20-dione, 16cc fiuoromethyl-4-pregnone-3,1 1,20-trione, 16a-fluoromethy1 4 pregnene-3,20- dione and the corresponding 20: and 6or-methyl analogue" thereof.

The llfl-hydroxy compounds (IX) thus produced are oxidized at the ll-position with chromium trioxide and pyridine or by other known methods, e.g., those previously described, to give the corresponding 16a-fluoromethyl-4-pregnene3,l1,20-triones (IX), e.g., l6oz-fiuoromethyl-4-pregnene-3,l 1,20-trione, Zea-methyl-16a-fluoromethyl- 4-prcgnene-3,l1,20-tri0ne, and 6a-1nethyl-loa-iuoromethyl-4-pregnene-3,1l,20-trione. These compounds representcd by Formula IX possess useful physiological activities, including anti-inflammatory, glucocorticoid, salt and water regulating, progestational, anti-fertility, cardiotonic and central nervous system depressant activities.

I4 ROUTE 2 Route 2 of this invention provides an alternate process for producing 16a-fiuoromethyl-4-pregnene-3,l1,20-trione (IXa).

According to the process of Route 2, 3a-hydroxy-l6- pregnene-ll,20-dione or a 3-acylate thereof (A-I), e.g., 3a-acetoxy-l6-pregnene-l1,20-dione, is treated with an alkali metal cyanide, e.g., potassium cyanide or sodium cyanide in a suitable solvent, e.g., those named in the cyanide reaction of Route 1, above, to produce 30t-hydroxy-l6a-cyano5fl-pregnane-l1,20-dione (A-II), which is then ketalized at the 20-position with a lower alkylene 06- or fi-glycol in the manner described in Route 1 for producing the compounds of Formula IV, to produce 3cL-hYCllOXY-l6rx-CYBJ1O-5 ,G-pregnane-l 1,20-dione 20-alkylene ketal (A-III). Compound A-IH is then hydrolyzed with an aqueous alkali-metal hydroxide, e.g., potassium or sodium hydroxide in a suitable organic solvent, e.g., ethylene glycol, to give 3rx-hydroxy-l6a-carboxy-55- pregnane-ll,20-dione 20-alkylene ketal which is then esterified with ethereal diazomethane to give 35-hydroxyl6a-carbomethoxy-iti-pregnane ZO-alkylene ketal (A- IV). This compound is then oxidized, e.g., with an N-haloamide or an N-haloirnide in pyridine, with chromic anhydride or chromium trioxide and dilute sulfuric acid in acetone or methylene chloride, with sodium dichromate in glacial acetic acid, or other known oxidizing agents to produce l6a-carbomethoxy-Sfi-pregnane 3,11,20 trione ZO-alkylene ketal which is then ketalized at the 3-position according to the procedures described in Route 1 for ketalizing the compounds of Formula III to produce 15oz carbomethoxy 5,8 pregnane 3,11,20 trione 3,20-bis(alkylene ketal) (A-V). This compound is then reduced with lithium aluminum hydride or other carboxyl reducing agent in the same manner as described in Route 1, above, to give ll B-hydroxy-l6 x -hydroxymethyl-5,B- pregnane-3,20-dione bis(alkylene ketal) (A-VI). This compound (A-VI) can be hydrolyzed by acid e.g., dilute aqueous sulfuric acid in acetone to give 11 fi-hydroxy-louhydroxyrnethyl-Sfi-preguane-3,20-dione. The 16a-hydroX- ymethyl group of AVI is then reacted with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride, to give the corresponding organic sulfonate of the l6m-hydroxymethyl derivative (AVII), e.g., the p-toluenesulfonate, which is then fluorinated by means of an alkali metal fluoride, e.g., anhydrous potassium fluoride, to produce 11,5 hydroxy 16c: fluoromethyl-5fi-pregnane-3,20-dione bis(alkylene ketal) (A-VIII). This compound is then oxidized by known methods for oxidizing the ll-position of steroids, e.g., hydrocortisone to cortisone, e.g., using chromium trioxide in pyridine, to produce to corresponding ll-keto compound which is then hydrolyzed under acid conditions to remove the ketal groups, e.g., dilute aqueous sulfuric acid, to give l6a-fiuoromcthyl-5fl pregnane-3,1l,20-trione (A-IX). This compound is then treated with a halogenating agent, e.g., a hypohalous acid, a mineral acid with a hypochlorite, such as t-butylhypochlorite, N bromoacetamide, N bromosuccinimide, N-chloroacetamide, l -chlorosuccinirnide and the like, to give the corresponding 4 halo 16a fluoromethyl 5B- pregnane-3,1l,20-trione. The 4-halo compound thus obtained can be converted to the corresponding A compound according to the procedure disclosed in US. Patent 2,794,814, e.g., by treatment with semicarbazide hydrochloride followed by pyruvic acid, to give 16CL-fll101'0- methyl-4-pregnene-3,l1,20-trione (IXa).

ROUTE 3 Route 3 of this invention provides another alternate procedure for producing l6a-fiuoromethyl-4-pregnene- 3,11,20-trione (IXa) and 3B-hydroxy-l6a-fiuoromcthyl-5- pregnen-ZO-one (A'IV) which is used as stalting material for production of the 6a-flu0r0 compounds of Group B of this invention.

According to the process of Route 3, 3,8-hydroXy-16acyano-5-pregnen-20-one is ketalized at the -position according to the method previously described in Routes 1 and 2 for ketalizing compounds of Formula III and A-II, to produce the corresponding 3p-hydroxy-i6ix-cyano-5- pregnen-ZO-one ZO-alkylene ketal (A-II), which is then hydrolyzed with an aqueous alkali-metal hydroxide, e.g., potassium or sodium hydroxide to give 3/i-hydroxy-16acarboxy-S-pregnen-ZO-one 20-alkylene ketal (A'III).

Compound A-III is then treated with dihydropyran in the presence of an acid catalyst, e.g., p-toluenesulfonic acid, concentrated sulfuric acid, bcnzenesulfonic acid, anhydrous hydrogen chloride and the like, to produce the corresponding 3-tetrahydropyranyloxy-16a-carboxy-5- preguen 2O one ZO-alkylene ketal tetrahydropyranyl ester. Reaction solvents which may be suitably employed in the dihydropyran reaction include benzene, toluene, Skellysolve B hexanes, xylene, diethyl ether, dioxane, chloroform, tetrahydrofuran and the like.

The tetrahydropyranyl ester is then reduced with lithi- 11m aluminum hydride or other carboxyl reducing agent in the same manner as described in Route 1, above, for reducing the compounds of Formula V to produce the corresponding 3-tetrahydropyranyloxy-l6ct-hydroxymethyl-S-pregnen-ZO-one ZO-slkylene ketal which is then reacted with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride to produce the corresponding organic sulfonate of the 16a-hydroxymethyl group, e.g., p-toluenesulfonate, which on fiuorination by means of an alkali metal fluoride, e.g., anhydrous potassium fiuoride gives the corresponding 3 tetrahydropyranyloxy 16oz fluoromethyl5-pregnen-20-one ZO-alkylene ketal. This compound is then hydrolyzed with dilute aqueous acid, e.g., sulfuric acid to give hydroxy 16a fiuoromethyl 5- pregnen-ZO-one (AIV).

This compound (AIV) is then oxidized (Oppenaur oxidation) with a ketone, e.g., acetone or cyclohexanone and an aluminum alkoxide, e.g., aluminum isopropoxide, to give 16u-fluoromethyl-4-pregnene-3,20-dlone (A'-V). This compound is then oxygenated at the ll-position by microbiological conversion, according to the procedure of US. Patent 2,735,800 for converting progesterone to llu-hydroxyprogesterone, to produce 11a-hydroxy-16w fiuoromethyl 4 pregnene-3,20-dione (A-VI), which is then oxidized at the ll-position by known methods, e.g., chromium trioxide and sulfuric acid, to produce 160:- fluoromethyl-4-pregnene-3,11,20-trione (IXa).

The compounds of Formula IX, i.e., 16a-fiu0romethyl- 4-pregnene-3,20-dione, 16ix-fiuoromethyl-4 -pregnene-3,11, 20-trione, 1lfi-hydroxy-16a-fluorornethyl-4pregnene-3,20- dione, and the corresponding 2a-methyl and 6ot-11'16thyl analogues, are converted to the corresponding cis and trans 4,l7(20)-pregnadien-"l-oic acid alkyl esters (X) according to the methods described in US. Patent 2,790,- 814. The compounds of Formula X are then converted to their 3-enarnines, reduced with an alkali-metal aluminum hydride, and hydrolyzed to remove the 3-enamine group, as described in U.S. Patent 2,781,343 to produce the 21-hydroxy compounds of Formula XI, i.e., cis and trans 115-2l-dihydroxy-16a-fiuorornethyl-4,17(20) pregnadien-3-one, 160a fluoromethyl-Zl-hydroxy 4,17(20)- pregnadien-3-one, and the 2a-methy1 and Got-methyl analogues thereof. The ll-keto group when present is simultaneously reduced to the 11fi-hydroxy group. The 21-free alcohols (XI) thus produced are esterified with an anhydride or acid halide of an organic carboxylic acid preferably a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms inclusive, including dicarboxylic acids, in pyridine or with an acid, e.g., formic, or an ester in the presence of an acid catalyst to produce the corresponding 21-acylate (XI).

The 21-acylates preferably the ZI-acetates of Formula XI are then oxidatively hydroxylated with osmium tctroxide and an amine oxide peroxide according to the procedure of US. Patent 2,769,825 or with an organic polyvulent iodo oxide, e.g., phenyliodoso acetate, according to the procedure of US. Patent 2,875,217 to give the com pounds of Formula XII.

The 11,8-hydroxy compounds of Formula XII, e.g., 1Got-fluoromethylhydrocortisone 21-acyl1xte and the corresponding Zea-methyl and ix-methyl analogues are oxidized in accordance with known methods for oxidizlng hydrocortisone ZI-acetate to cortisone 21-acetate, c.g., chromic anhydride and acetic acid, chromium trioxide and sulfuric acid, N-haloimides or N-haloamides, etc., to produce the corresponding ll-keto compounds of Formula XIII.

The compounds of Formulae XII and XIII are then converted to the corresponding 2l-Iree alcohols (XIV) by hydrolysis in accordance with known methods for hydrolyzing hydrocortisone ZI-acrylates to hydrocortisone, e.g., sodium or potassium bicarbonate in aqueous alcohol, in an oxygen-free atmosphere.

The compounds of Formula XIV, are dehydrogenated at the 1,2-position by fermentative or chemical dehydrogenation to give the corresponding l-dehydro compounds of Formula XV. Fermentative dehydrogenation comprises the use of micro-organisms such as Septomyxa, Corynebacterium, Fusarium, and the like, under fermentation conditions well known in the art (e.g., US. 2,602,769, 2,902,410 or 2,902,411}. When Septomyxa is used to effect the dehydrogenation it is found to be advantageous to use with the substrate and medium a steroid promoter, such as progesterone, 3-ketobisnor-4-cholen-22-al, 3-ket0- bisnorcholenic acid, 11,8,21-dihydroxy-1,4,17(20)-pregna trien-3-one, and the like. The free alcohols are usually employed as starting material for the fermentative dehydrogenation process. However, 21-acylates of Formulae XII and XIII can be used. In these cases the 2l-ester group is generally saponified during the fermentation process giving the corresponding 21-free alcohol represented by Formula XV. Chemical dehydrogenation can be carried out with selenium dioxide according to procedures well known in the art [e.g., Meystre et a1., Helv. Chim. Acta, 39, 734 (1956)]. The 21-acylates of Formulae XII and XIII are generally preferred as starting material in the chemical dehydrogenation reaction giving the corresponding 21-acylate represented by Formula XVI. The 2l-acylate thus obtained can be saponified, if desired, by methods known in the art to give the corresponding 21-free alcohol (XV).

The compounds of Formula XIV and XV are reesterified to the corresponding 2l-acylates by reaction with the selected acylating agent. This reaction can be performed under the esterification conditions known in the art, e.g., by the reaction of XIV or XV w'th the selected acid chloride or acid bromide or the anhydride of an organic carbox-ylic acid, or by reaction w th the selected acid in the presence of an esterification catalyst, for example, p-toluenesulfonyl chloride, trifiuoroacetic anhydride, p-toluenesulfonic acid, trifiuoroacetic acid, sulfuric acid, and the like, or with an ester under ester exchange reaction conditions. Compounds thus produced include those wherein Ac is the acyl radical of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., the acids listed in Example 36A.

Group B.The novel compounds of Group B of this invention are represented by the following Formulae:

17 18 wherein R and X have the same meanings as previously The processes for the production of the compounds of given. Group B of the present invention are illustratively represented by the following reaction scheme:

XVII

i CH3 Q-OAc =0 l- L .0H I "CHIF 011m no A00 XIX XVIII on: 111; E 0=0 0:0 1 i ---OH -oH l i 011,1 i I E A00 A00 XX XXI i 0' Ho onnzr on,

:0 --0H -on i "011m --0H,F

: I XXIII Y XXII I 116 F 110 F CH OAc t me 0: C=O IKOH "0H --0H,I --0HIF XXIV a XXV Ho F 110 F (EH: R3 2 3 0:0 0: |--OH -OH 110M orm --0H,F

. XXVII XXVI crnon; r zrnon g I --o H --OH 5 I O "CHQF X3 CHQF E i I t l i xxvm 0 XXIX i I l I \\u l I 2 omoac X3 "cum 0 XXX wherein X is the methylene radical, the carbonyl radical or the hydroxymethylene radical and wherein Ac and R have the same meanings as previously given. In this application the wavy line appearing at the ll-position denotes either the a or ,8 configuration or mixtures thereof.

The process of preparing the compounds of Group B of the present invention involves esterifying 3B-hydroxy-l6afiuoromethyl-S-pregnen--one (A-IV), e.g., with acetic anhydride and a strong acid catalyst, to produce 35,20- dihydroxyl 6a-fluoromethyl-5, 1 7 (20 -pregnadiene 3 ,20- diacetate (XVII) which is then converted, preferably without isolation, with a peracid, e.g., peracetic or perbenzoic acid, to 3 8,20-dihydroxy-5a,6a,17a,20-diepoxyl6a-fluoromethylpregnane 3,20 diacetate (XVIII), in exactly the manner that pregnenolone has been converted to the diepoxi-de of its 3,20-diacetate. This compound is hydrolyzed, preferably without isolation, with aqueous base, e.g., sodium hydroxide or potassium hydroxide, to produce 3/3-1'loc-(lihYdlOXY-Su,6nt-6POXY-16or-flUOIOIn6thylpregnan-ZO-one (XIX). A by-product in the above series of reactions is the corresponding 55,6,8-epoxide. This compound is desirably separated from the desired ,6LZ- epoxide, e.g., by fractional crystallization of XVIII or by converting the mixture of XIX and the corresponding 53, 6fi-epoxide to a 3-acylate thereof (XX), e.g., formate, acetate, trifiuoro acetate, benzoate, preferably a lowerhydrocarbon acylate, and separating these epoxides, e.g., by known methods of chromatography or fractional crystallization. The epoxidc opening step is carried out according to the procedure of U.S. Patent 2,83 8,497, Le, 38, 17a-dihydroxy-5 a,6a-epoxy-16a-fluoromethylpregnan 20- one (XIX) or a 3-acylate thereof (XX) is converted with anhydrous hydrogen fluoride in chloroform or methylene chloride in the presence of tetrahydrofuran at 60 C. to +20 C., or aqueous hydrogen fluoride, e.g., at 0 to 30 C., to 313,5a,l7a-trihydroxy-6fl-fluoro-l6or-fiuoromethylpregnan-20-one (XXII) and 3fl,5a,l7a-trihydroxy- 6B-fluoro-16a-fiuoromethylpregnan 20 one 3 -acylate (XXI), respectively. The latter compound (XXI) is hydrolyzed with aqueous acid, e.g., hydrochloric, sulfuric or boron t-rifiuoride in methanol, to produce the former compound (XXII), which is then brominated, e.g., with a molar equivalent of bromine in chloroform or acetic acid to produce 3,3,5a,17a-trihydroxy-6fl-fluoro 16a fluoromethyl-2l-bromopregnan-ZO-one (XXIII). Reaction of this compound with alkali-metal lower-hydrocarbon acylate, e.g., potassium acetate, sodium acetate, sodium formate, sodium propionate, potassium fi-cyclopentylpropionate, sodium benzoate, etc., is productive of 3/3,5a,l7u,21- tetrahydroxy-fia-fluoro-16or-tluoromethy1pregnan-20 one 2l-acylate ()OiIV). Oxidation of this compound with sodium dichrornate in glacial acetic acid, chromic anhydride and aqueous sulfuric acid in acetone or methylene chloride or an N-haloamide or N-haloimide in pyridine is productive of 5a,17a,21-trihydroxy-6p-fluoro-1Got-fluoromethylpregnane-3,20-dione 21-acylate (XXV). Reaction of this compound with acid, e.g., hydrogen chloride in CHCl preferably in the presence of less than 2% of a lower-alkanol, e.g.,.ethanol or t-butyl alcohol, is productive of 60a fluoro-16a-fluoromethy1-17a,21-dihydroxy-4- pregnene-3,20-dione 21 acylate (XXVI), which is hydrolyzed with base according to known procedures, e.g., the hydrolysis of hydrocortisone 21-acylates to hydrocortisone, to give 6a-fluo'ro-16a-fluoromethyl-l7u,2l-dihydroxy-4-pregnene-3,ZO-dione (XXVI).

The 6a-fiuora-16u-fluoromethyl-17a,21 dihydroxy-4- pregnene-3,20-dione or a 2l-acylate thereof (XXVI) is then converted to 6a-fluoro-16u-fiuoromethylhydrocortisone and the 21-acylates thereof (XXVII), by reaction with an llfi-hydroxylating species of fungus, e.g., Cunninghamella blakesleeana, Curvularia lnata, Trichothecium roseum, etc., according to procedures well known in the art, e.g., US. Patent 2,602,769. The free alcohol (XXVI) is usually employed as the starting material in the fermentation reaction, however the 21-acylates (XXVI) can be used. In these cases the 21-ester is generally saponified during the fermentation to give the 21- free alcohol (XXVII), which can be reesterified by known 21-esterification methods.

Alternatively 6a-fiuoro-16a-fluoromethyl-17u,2l-dihydroxy-4-pregnene-3,20-dione or a 21-acylate thereof (XXVI) can be converted to 6a-fltIO1O-lla,17oc,21-trihydroxy-l6a-fiuoromethyl-4-pregnene-3,ZO-dione or a 21- acylate thereof (XXVII) by reaction with an Ila-hydroxylating species of fungus, according to the procedure of US. Patent 2,735,800 for converting 170:,21-dihYd1OXY- 4-pregnene-3,20-dione to 11a,17a,21-trihydroxy-4-pregnene-3,20-dione. The free alcohol (XXVI) is usually employed as the starting material, however the 21-acylates can be used. In these cases the 21-ester is generally saponified during the fermentation giving the free alcohol (XXVII), which can be reesterified at the 21-position by known selective 21-esterification methods, e.g., US. Patent 2,735,800.

The GwflUOrO-l6oc-fluOIOIllEthYlhYdI'OCOItISOHB, 6a-fiuoro 1I0z,17x,2l trihydroxy 16oz fluorornethyl 4 pregnone-3,20-dione or the 21-acylates thereof (XXVII) are then oxidized to 6zx-fluoro-16a-fluoromethy1cortisone or the corresponding 2l-a-cylate, respectively, in accordance with known methods for oxidizing the lle-hydroxy group to the ll-keto group hereinbefore described, e.g., N-bromacetamide or chromic acid.

The compounds of Formulae XXV-I, XXVII and XXVIII are dehydrogenated at the 1,2-position by fermentative or chemical dehydrogenation. Fermentative dehydrogenation comprises the use of microorganisms such as Septomyxa, Corynebacterium, Fusarium, and the like, under fermentation conditions well known in the art (e.g., US. 2,602,769, 2,902,410 and 2,902,411). Where Septomyxa is used to eifect the dehydrogenation it is found to be advantageous to use with the substrate and medium a steroid promoter. The free alcohols are usually employed as starting material for the fermentative dehydrogenation process. However, the corresponding 21-acylates can be used. In these cases the 21-ester group is generally saponified during the fermentation process giving the corresponding free alcohol. Chemical dehydrogenation can be carried out with selenium dioxide according to procedures well known in the art [e.g., Meystre et al., Helv. Chim. Acta, 39, 734 (1956)]. The ZI-acylates are generally preferred as starting material in the chemical dehydrogenation reaction giving the corresponding compounds of Formula XXX. The 21-acylates thus obtained can be saponified, if desired, by methods known in the art to give the corresponding 21- free alcohols.

Group C.The novel 9e-halocortisones and 21-acylates thereof of Group C of this invention are represented by the following formulae:

wherein Y, Y and R have the same meanings as previously given, X is the ,B-hydroxymethylene radical or the carbonyl radical, Z is halogen having an atomic weight from 19 to 127, inclusive, i.e., fluorine, bromine, chlorine or iodine.

The processes for the production of the compounds of Group C of this invention are illustratively represented by the following reaction scheme:

in 7 XISIIEXXI is combined from Formulae XII, XVI, XV II and XXXVII wherein X, Y, Y Z and Ac have the same meanings as previously given and Z is a halogen having an atomic weight from 35 to 127, inclusive, i.e., bromine, chlorine or iodine. The dotted line appearing in Formulae XXXI to X)O(VH represents a A double bond which may or may not be present.

The Qua-halo compounds of Group C of this invention are prepared according to the procedure of U8. Patent 2,852,511 as follows: dehydrating 16a-fiuoromethy1hydrocortisone 21-acylate (XXXI) or the corresponding 20:- methyl, 6OL-I1'1thy1 or 6a-fluoro analogues thereof, or 1- dehydro 16a fluoromethylhydrocortisone 21 acylate (XXXI) or the corresponding 2-methyl, Got-methyl or 60tfluoro analogues thereof, represented by Formula XXXI, with an N-haloamide, e.g., N-bromoacetamide in pyridine followed by anhydrous sulfur dioxide produces the corresponding A901) compounds (XXXII), i.e., 16a-fiuoromethyl-17a,21-dihydroxy 4,9(11) pregnadiene 3,20- dione 21-acylate, the Zea-methyl, 6a-methyl and 6a-fiuoro analogues thereof and the corresponding 1,4-pregnadienes, respectively. Addition of a hypohalous acid, i.e., hypo bromous, hypochlorous or hypoiodous, to these latter compounds produces the corresponding 9a-halo compounds (XXXIII), i.e., 9u-halo-16a-fluoromethy1hydrocortisone 21-acylate, the Zea-methyl, 6a-methyl and 6afiuoro analogues thereof and the corresponding l-dehydrocompounds, respectively, which by treatment with base, e.g., anhydrous potassium acetate, yield the corresponding epoxy compounds (XXXIV), i.e., 16a-fluoromethyl-9fi, 11B epoxy 17a,21-dihydroxy-4-pregnene-3,20-dione 21- acylate, the 2a-methyl, 6a-methyl and Got-fillOl't) analogues thereof and the corresponding 1,4-pregnadienes, respectively. Treatment of these epoxy compounds with hydrogen fluoride or other hydrogen fluoride releasing agents produces the corresponding 9a-fluoro compounds (XXXV), i.e., 9a-fluoro-16or-fluoromethylhydrocortisone 21-acylate, the Zea-methyl, 6OL-I'1'16thy1 and 6a-fll101'0 analogues thereof and the corresponding l-dehydro compounds, respectively. Oxidation of the llfl-hydroxy compounds represented by Formulae XXXIII and X)O(V, preferably the ZI-acetates with, e.g., chromic acid in acetic acid provides the corresponding ll-keto compounds (XXXVI), e.g., 9a-fluoro- 16a-fiuoromethyl-cortisone 21-acylate, the Zea-methyl, 6mmethyl and oa-fiuoro analogues thereof, the corresponding l-dehydro compounds and the other corresponding 90:- bromo, 9rx-chloro and 9a-i0d0 ll-keto compounds represented by Formula XXXVI. Hydrolysis of the ZI-esters of Formulae XXXIII, XXXV and XXXVI with a base, e.g., aqueous sodium hydroxide or sodium bicarbonate, provides the corresponding free 21-alcohols represented collectively by Formula XXXVII, e.g., 9a-fluoro-16afluoromethylhydrocortisone, 9a-fiuoro-16u-fiuoromethylcortisone, 1 dehydro 90c fluoro-l6a-fluoromethylhydrocortisone, l-dehydro-9a-fiuoro-16a-fiuoromethylcortisone, the corresponding Zea-methyl, 6a-methyl and 60:- fiuoro analogues thereof and the other corresponding 90:- bromo, 9a-chloro and 9a-iodo 21-free alcohols represented by Formula XXXVII.

The 21-free alcohols (XXXVII) thus produced can be reesterified by known 21-acylation methods to produce the corresponding 21-acylates wherein the acyl radical is that of an organic carboxylic acid, preferably that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., those acids named in Example 36A.

Alternatively the A -compounds represented by Formula XXXVII and the 21-acylates thereof can be converted to the corresponding A -compounds by known fermentative or chemical 1,2-dehydrogenation procedures hereinbefore described in Groups A and B, above, e.g., using Septomyxa (US. Patents 2,902,410 and 2,902,411) or selenium dioxide.

Group D.The novel 21-desoxy and 21-fluoro compounds of Group D and the l7-acylates thereof are represented by the following formulae:

$11 115 (3112116 :0 C=O om X2 ems I Y-- I Y O- O in Y1 wherein R Y, Y X and Z have the same meanings as previously given, R is hydrogen or fluorine and wherein when X is the methylene radical Z is hydrogen.

The processes for the production of the compounds of Group D of this invention are illustratively represented by the following reaction scheme:

XLIV

XLV 3 51 *Formuln XXXVIII is combined from Formulae XIV, XV, 75 XXVI, XXVII, XXVIII, XXIX and XXXVII.

XLIII wherein Ac, R Y, Y X and Z have the same meanings as previously given and wherein when X is the methylene radical Z is limited to hydrogen. The dotted line appearing in Formulae XXXVIII to XLV represents a A double bond which may or may not be present.

The 21-fluoro compounds of Group D of the invention are prepared according to the procedure of U.S. Patents 2,838,535 or 2,838,543, i.e., by treating the compounds of Formula XXXVIII with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonyl chloride, naphthylenesulfonyl chloride, or the like, to obtain the corresponding 21-sulfonate (XXXIX), treating the thus-produced 21-alkyl or aryl sulfonate (XXXIX) with sodium iodide in acetone solution to obtain the corresponding 21- iodo compounds (XL), treating the thus-obtained 2l-iodo compounds with silver fluoride, preferably in acetonitrile solution to obtain the corresponding 2l-fiuoro compounds (XLI). Alternatively, the ZI-sulfonate (XXXIX), preferably the 21-methylsulfonate, can be treated directly with potassium fluoride in dimethyl sulfoxide, to produce the 2l-fiuoro compounds directly. When this alternate process is employed, the corresponding 17,21-epoxy compounds (XLII) are concomitantly produced.

The Ill-unsubstituted compounds of the present invention are prepared according to the procedure of U.S. Patents 2,838,541 or 2,838,542, i.e., by treatin a 21-iodo compound (XL), with a reducing agent such as sodium thiosulfate, sodium bisulfite, potassium bisulfite, or the like, in an aqueous organic solvent mixture, to obtain the corresponding 21-unsubstituted compound (XLIV).

Alternatively 16cc fiuoro-rnethyl l7a-hydroxy-4-pregnene-3,20-dione (XLIV), is prepared by treating the selected 3 B, 17a-dihydroxy-5u,6m-epoxyl 6rx-fiuoromethylpregnan-ZO-one S-acylate (XX) with zinc and sodium iodide in acetic acid to produce the corresponding 3,8,17adihydroxy 16a-fiuoromethyl-5-pregnen-20-one 3-acylate which is then hydrolyzed by known methods, e. g., aqueous sodium hydroxide to give the free alcohol, 3fl,17u-dihydroxy-16a-fluoromethyl-5-pregnen-20-0ne, which is then oxidized (Oppenauer oxidation) with an aluminum alkoxide, e.g., aluminum isopropoxide to give l6a-fiuoromethyl-l7a-hydroxy-4-pregnene-3,ZO-dione (XLIV). Preferably the 3,8,17ca-dihydroxyd6a-fluoromethyl-S-pregnen-ZO- one is dissolved in acetone and oxidized with aqueous chromic acid in the presence of sulfuric acid and then isomerized with, e.g., oxalic acid or dilute alkali to give 160: fiuoromethyl 17a hydroxy 4 pregnene 3,20- dione (XLIV).

The compounds of Formulae XLI and XLIV as esterified at the 17-position according to known 17-esterification methods, e.g., an acid anhydride in the presence of an esterification catalyst, e.g., acetic anhydride and p-toluenesulfonic acid, to produce the corresponding 17-acylates (XLIII and XLV), respectively, wherein the acyl radical is that of an organic carboxylic acid, preferably that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive, e.g., those acids listed in Example 36A.

Alternatively the 9a-halo compounds represented by Formulae XLI and XLIV wherein X is fi-hydroxy and Z is halogen can be prepared by converting the corresponding compounds of Formulae XLI and XLIV, respectively, wherein Z is hydrogen to the corresponding 90:- halo compounds via the 9(11)-dehydro compound in the manner described hereinbefore in Group C above.

Alternatively the Ar -compounds of Formulae XLI and XLIV, and the 17-acylates thereof (XLIII) and (X LV), can be converted to the corresponding n -compounds by known fermentative or, preferably, chemical 1,2-dehydrgenation procedures hereinbefore described in Groups A and B, above, e.g., using Septomyxa (U.S. Patents 2,902,- 410 and 2,902,411) or selenium dioxide.

Alternatively, the compounds of Formulae XLI and XLIV and the 21-acylates thereof (XLIII and XLV) wherein X is the carbonyl radical can be prepared by oxidation of the corresponding llfi-hydroxy compounds by methods known in the art for the oxidation of hydrocortisone acetate to cortisone acetate, e.g., chromic acid, N-bromoacetamide and the like.

PREPARATION 1 oat-methylpregnane-3,11,20-tri0ne A mixture containing 0.5 g. of 6a-methyl-11-ketoprogesterone, t-butyl alcohol and mg. of 5% palladium on charcoal as a catalyst is hydrogenated at a pressure of about 15 psi. (gauge) in a Parr hydrogenation apparatus. When the uptake of hydrogen ceases, the reaction mixture is filtered to remove the catalyst and concentrated. The residue thus obtained is recrystallized from acetone: Skellysolve B hexanes to give 6a-rnethylpregnane-3,11,20- trione, a light colored crystalline solid. Alternatively, if desired, the residue may be purified by chromatography.

In the same manner substituting as the starting steroid in Preparation 1, 2a-methyl-1l-ketoprogesterone, Gut-methylprogesterone or 2a-methylprogesterone, there is thus produced, 2a-methylpregnane-3,11,20-tri0ne, Got-methylpregnane-3,20-dione and 2a-methylpregnane-3,20-dione, respectively.

PREPARATION 2 3,2=0-diacetoxy-6ot-methy[-3,] 7(20 -pregnadien-11-one A mixture of 300 mg. of 6a-methylpregnane-3,11,20-trione, 15 ml. of acetic anhydride and mg. of p-toluene sulfonic acid monohydrate is heated to boiling and allowed to distill slowly until most of the excess acetic anhydride is distilled. The last traces of excess acetic anhydride are removed under vacuum, and the resulting resi due is cooled and dissolved in ether. The ether solution is washed with cold 10% aqueous sodium bicarbonate solution and dried over sodium sulfate. The ether is then evaporated to give a residue of 3,20-diacet0xy-6amethyl-3, 17 20) -preguadien-1 l-one.

PREPARATION 3 4,1 7a-dz'brom0-6a-methylpregnane-3J1,20-tri0ne mg. of 3,20-diacetoxy-6u methyl-3,17(20) pregnadien-ll-one 'is dissolved in t-butyl alcohol and treated with a solution of 125 mg. of N bromosuccinimide in 15 ml. of t-butyl alcohol and with 5 ml. 1 N sulfuric acid. The mixture is allowed to stand at room temperature until the reaction is complete. The reaction mixture is then concentrated in vacuo, diluted with water and the resulting product collected on a filter. Recrystallization from alcohol gives 4,17a-dibromo-6a-methylpregnane-3,11, 20- trione, a light colored crystalline solid.

PREPARATION 4 6u-methyZ-1 7u-br0m0-4-pregnene-3,11,20-tri0ne A solution of 1 =rnillimole of 4,17a-dibromo-6a-methylpregane-3,l1,20-trione dissolved in dioxane i-s admixed with 2.5 ml. of an aqueous solution containing 2 millimoles of semioarbazide and 2 millimoles of 'anhydrous sodium acetate. The mixture is stirred overnight at room temperature and thereafter .a solution of 0.52 g. of pyruvic acid in 5 ml. of water is added. The reaction mixture is then heated to about 70 C. for a period of about 3 hours, cooled and poured into water. The thus produced 6a methyl-l7a bromo-4-pregnene-3,11,20-trione is extracted from the aqueous mixture with methylene chloride. The extracts are combined, washed with 1% aqueous sodium hydroxide solution, and water until the wash water is neutral, dried over anhydrous sodium sulfate and concentrated. The residue is purified by chromatography over 'Florisil (synthetic magnesium silicate) and recrystallized from acetonezSkellysolve B hexanes to give 6arnethyl-l7a-bromo-4-pregnene 3,1 1,20-trione, a light colored crystalline solid.

2'? PREPARATION 6a-methyl-4,16-pregnadienc-3,J1,20-Iri0ne 1.0 g. of 6a-methyl-l7a-bromo-4-pregnene-3,11,20-trione is dissolved in dry pyridine and heated under reflux for a period of about 24 hours. The pyridine is then removed by distillation at reduced pressure and the residue thus obtained is dissolved in benzene. Water is then added to the benzene solution and the layers are separated. The benzene layer is washed with dilute hydrochloric acid and water until neutral, dried over anhydrous magnesium sulfate, and concentrated to dryness at reduced pressure. The residue thus obtained is recrystallized from ethyl acetate in Skellysolve B hexanes to give 6tx-methyl-4J6- pregnadiene-ll1,20-trione, a light colored crystalline solid.

In the same manner substituting as the starting steroid in Preparation 2 the other pregnanes prepared and named in the second paragraph of Preparation 1 and following the procedures of Preparations 2 through 5, consecutively, there are thus produced as products of Preparation 5 the corresponding 4,16-pegnadienes as light colored crystal line solids, i.e., 2a-methyl-4,16-pregnadiene-3,l1,20-trione, 6u-methyl-4,16 pregrandiene-3,20-dione and 2amethyl-4,16-pregnadiene-3 ,20-dione, respectively.

The following examples are illustrative of the processes and products of the present invention.

EXAMPLE 1A 4,] 6-pregnadiene-3,1.I,20- rione 3-ethylene ketal (II) A mixture of 31.68 g. of 4,'16 pregnadiene-3,11,20-trione (I), 500 ml. of Z-methyl-Z-ethyldioxolane, and 300 mg. of p-toluenesult'onic acid monohydrate was heated to reflux for a period of about 4 hours. Water was removed during the reflux period by use of a water separator. The reaction mixture was cooled and methylene chloride was added. The methylene chloride solution was washed consecutively with sodium bicarbonate solution and water and then dried over sodium sulfate. The methylene chloride was then removed by evaporation and the resulting residue was dissolved in benzene and chromatographed on 1000 g. of acid-washed alumina. The column was eluted with increasing proportions of ether in benzene; crystalline material was obtained from the eluates containing up to 50% etherzbenzene. The crystalline material thus obtained was combined and recrystallized from acetonezSkellysolve B hexanes to give 8.5 g. of 4,l6-pregnadiene-3,11,20-trione '3-ethylene ketal melting at 228-233 C. A second crop of crystals was obtained from the mother liquors giving 1.0 g. of 4,16-prcgnadiene- 3,11,20-trione 3-ethylene ketal melting at 2052l1 C. The crystalline material was combined and recrystallized from acetoneaSkellysolve B hexanes to give 4,16-pregnadiene-3,ll,20-trione 3-ethylene ketal (II) melting at 233-235 C.;

max.

my, ar

The infrared absorption sepctrum agreed with the assigned structure.

Analysis.Calcd. for C H O C, 74.56; H, 8.16. Found: C, 74.43; H, 8.37.

EXAMPLE 1A 4,16-pregnadicne-3,11,20-tri0ne 3-ethylene ketal (I!) and dried over anhydrous sodium sulfate. The dry benzene solution was evaporated until crystallization occurred to give 44.0 g. of 4,16-pregnadiene-3,l1,20-trione 3-ethylene ketal (II) melting at 215230 C. The mother liquors from the crystallization were chromatographed on 2 kg. of llorisil synthetic magnesium silicate. The column was eluted with inceasing proportions of acetone in Skellysolve B hexanes. The eluates containing from 7% acctone:Skellysolve B hexanes to 10% acetone: Skellysolve B hexanes gave an additional 34.3 g. of 4,16 pregnadienc-3,l1,20-trione 3-ethylene ketal (II).

In the same manner, following the procedure of Ex amples 1A or 1A but substituting as starting material other compounds of Formula I, i.e., 4,16-pregnadiene-3, 20-dione, 2a-methyl-4,16-pregnadiene 3,11,20 trione, 2a-methyl-4,16-pregnadiene-3,20-dione, 6a-methyl-4,l6- pregnadiene-3,11,20-trione or 6a-methyl-4,l6-pregnadiene-3,20-dione, is productive of the 3-ethylene ketals represented by Formula II, i.e., 4,16-pregnadiene-3,20dione 3-ethylene ketal, 2a-methyl-4,l6 pregnadiene-3,ll,20- trione 3-ethylene ketal, 2a-methyl-4,l6-pregnadiene-3,20- dione 3-ethylene ketal, 6a-methyl-4,'16-pregnadiene-3,l1, 20-trione 3-ethylene ketal and 6a-methyl-4,1.6-pregnadiene-3,20-dione 3-ethylene ketal, respectively.

EXAMPLE 2A 16ot-cyan0-4-pregncite-3,11,20-tri0na 3-etlzy lene ketal (III) A mixture of 9.5 g. of 4,l6-pregnadiene-3,l1,20-trione 3-ethylene ketal (II), 15.0 g. of potassium cyanide, ml. of dioxane and 500 ml. of methanol was heated in a nitrogen atmosphere under reflux for 3 hours. The reaction mixture was cooled, poured into about 2 liters of water, and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained was dissolved in benzene and filtered through a column containing 20 g. of acid-washed alumina which had been previously wetted with benzene. The eluate was evaporated to remove the benzene and the residue was recrystallized from acetone: Skellysolve B hexanes to give 6.15 g. of 16ot-eyano-4-pregnene-3J1,20- trione 3ethylene ketal (III) melting at 236-242 C. The product thus obtained was recrystallized twice from acetonezmethanol to give cyano 4 pregnene-3,11,20- trione 3-ethylene ketal (III) melting point at 224244 C. The infrared spectrum agreed with the assigned structure. Optical rotatory dispersion analysis indicated that the compound had the 17,B-configuration.

Analysis.-Calcd. for C H O N: C, 72.51; H, 7.86. Found: C, 72.49; H, 7.94.

EXAMPLE 2A 1fiwcj/anO- l-[Jreguene-3,11,ZO-lrione 3 -et/zylene ketal (III) A mixture of 63.3 g. of 4,l6-pregnadiene-3,11,20-trione 3-ethylene ketal (II), 75.0 g. of potassium cyanide, 2.5 liters of methanol and 450 m1. of dioxane was heated under reflux in a nitrogen atmosphere for a period of about 3 hours. At the end of the refiux period the reaction mixture, was cooled to room temperature and the solvent was removed in vacuo until crystallization occurred. Two liters of water was then added and the mixture was stirred for a few minutes; the crystalline material thus obtained was collected on a filter, washed With water and dried in vacuo at room temperature giving 47.0 g. of 16a-cyano-4-pregnene-3,11,20-tri0ne 3-ethylene ketal melting at 237- 242 C.

In the same manner, following the procedure of Example 2A or 2A but substituting as starting material other 4,l6pregnadiene 3-ethylene ketals, represented by Formula II, i.e., those listed in the second paragraph of Example 1A for 4,16-pregnadiene-3,11,20-trione 3-ethylene ketal is productive of the corresponding l6a-cyano compound represented by Formula Ill, i.e., l6ct-cyano-4- pregnene 3,20 dione 3 ethylene ketal, 2ot-methyl-l6acyano 4 pregnene 3,11,20-trione 3-ethylene ketal, 2ozmethyl 16oz cyano 4 pregnene-3,20-dione 3-ethylene ketal, 6a methyl 16cc cyano-4-pregnene-3,l1,20-trione 3 ethylene ketal and 6a methyl-16a-cyano-4-pregnene- 3,20-dione 3-ethylene ketal, respectively.

EXAMPLE 3A 16a-cyan0-4-pregnens-3,11,20-tri0ne 3,20-bis (ethylene ketal) (IV) A mixture of 1.1 g. of 16a-cyano-4-pregnene-3,l1,20- trione 3-ethylene ketal (III), 150 ml. of benzene, 3.0 ml. of ethylene glycol and 25 mg. of p-toluenesulfonic acid monohydrate was heated to boiling under reflux for a period of about 6 hours. Water was removed during the reflux period by incorporating a conventional water separator to the reflux condenser. The reaction mixture was then cooled and sodium bicarbonate solution was added. The organic layer was separated, washed with water, dried over sodium sulfate and the solvent was removed in vacuo. The residue thus obtained was recrystallized from acetone: Skellysolve B hexanes giving 640 mg. of 16a-cyano-4-pregnene-3,ll,20-trione 3,20-bis(ethylene ketal) (IV) melting at 251-253 C.

In the same manner, following the procedure of Example 3A but substituting as starting material other 16acyano-4-pregnene 3-ethylene ketals, represented by Formula III, i.e., those listed in the second paragraph of EX- ample 2A, for l6a-cyano-4-pregnene-3,11,20-trione 3- ethylene ketal is productive of the corresponding bis(ethylene ketal) represented by Formula IV, i.e., l6ot-cyano-4- pregnene-3,20-dione bis (ethylene ketal), 2a-methyl-16acyano-4-pregnene-3,11,20-trione 3,20bis(ethylene ketal), 2a. methyl-l6u-cyano-4-pregnene-3,20-dione bis( ethylene ketal), 6a-methyl-16a-cyano-4-pregnene-3,l1,20-trione 3, 20-bis(ethylene ketal) and 6a-methyl-16a-cyano-4-pregnene-3,20-dione bis(ethylene ketal), respectively.

EXAMPLE 4A 16a.-cyan0-4-pregnene-3,1l,ZO-trione (16a-cyan0- 1 1 -ketpr0gesterone) (Illa) A solution of 1.01 g. of l6a-cyano-4-pregnene-3,11,20- trione 3-ethylene ketal (III) in acetone containing ml. of water and 3 drops of 25% sulfuric acid was allowed to stand for a period of about 18 to 24 hours at room temperature. Sodium bicarbonate solution was then added and the acetone was removed in vacuo at room temperature until crystallization commenced. An additional 100 ml. of water was then added, the temperature of the mixture was lowered to 0 C. and crystallization was allowed to proceed. The solid material was collected by filtration, dried, and crystallized twice from acetone:Sl-:ellysolve B hexanes to give 500 mg. of 16m-cyano-4-pregnene-3,l1,20- trione melting at 230235 C. A final crystallization from methanol raised the melting point to 238240 C.,

EtOH max.

The infrared spectrum supported the assigned structure. Optical rotatory dispersion analysis showed the 17 8-side chain.

Analysis.Calcd. for C H O N: C, 74.75; H, 7.70. Found: C, 14.63; H, 7.60.

In the same manner, following the procedure of EX- ample 4A but substituting as starting material other 16acyano-4-pregnene 3-ethylene ketals represented by Formula III, i.e., those compounds listed in the second para graph of Example 3A, for 16a-cyano-4-pregnene-3J1,20- trione 3-ethylene ketal is productive of the corresponding free 3-keto compound represented by Formula IIIa, i.e., 16oz cyano 4 pregnene 3,20-dione, 2a-methyl-16ccyano 4-pregnene-3,11,20-trione, 2a-methyl-16ot-cyano-4- pregnene 3,20 dione, 6a-methyl-l6a-cyano-4-pregnene- 3,11,20 trione and 6a methyl l6a-cyano-4-pregnene- 3,20-dione, respectively.

EXAMPLE SA 16a cal-boxy 4-pregnene-3J1,ZO-trione 3,20-liz's(ethylene ketal) (V) and 16a-carb0meth0xy-4-pregnene-3JI, 20-Irzi0ne 3,20-bz's(ethylene ketal) (V) A mixture of 13.7 g. ofl6ot-cyano-4-pregnene-3,l1,20- trione 3,20-bis(ethylene ketal) (IV), 400 ml. of ethylene glycol and 25 g. of potassium hydroxide dissolved in ml. of water was heated to reflux in a slow stream of nitrogen for a period of about 20 to 24 hours. After cooling, water was added and the alkaline solution was extracted with methylene chloride. The aqueous layer was then cooled to 0 C., carefully acidified to about pH 4 and rapidly extracted with ethyl acetatezmethylene chloride. The combined ethyl acetatezmethylene chloride extracts were washed with water until netural, dried over sodium sulfate and the solvent removed by evaporation to give a residue comprising 16a-carboxy-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal) melting at 225-245 C. which can be purified by either chromatography or crystallization on both to give l6ot-carboxy4-pregnene-3,l1,20. trione, a crystalline solid.

The residue thus obtained was dissolved in 200 ml. of methylene chloride and 500 ml. of methanol and esterified with excess ethereal diazomethane solution for 3 hours at room temperature. The solvent was removed by evaporation and the residue thus obtained crystallized from acetonezSkellysolve B hexanes to give 9.8 g. of 16a-carbomethoxy 4 pregnene-3,11,20-trione 3,20-bis (ethylene ketal) melting at about 200 C. Two recrystallizations from the same solvent gave l6ot-carhomethoxy-4- pregnene-3,11,20-trione 3,20-bis(ethylene ketal) (V) melting at 224-225 C. The infrared spectrum agreed with the assigned structure.

Analysis.-Calcd. for C H O z C, 68.33; H, 8.07. Found: C, 68.29; H, 7.94.

In the same manner, following the procedure of EX- ample 5A but substituting as starting material other 16a-cyano-4-pregnene 3,20-bis (ethylene ketals) represented by Formula IV, i.e., those listed in the second paragraph of Example 3A for 16a-cyano-4-pregnene-3,11,20- trione 3,20-bis(ethylene ketal), hydrolysis with potassium hydroxide is productive of the corresponding 16a-carboxy compound represented by Formula V, i.e., 16a-carboxy-4- pregnene-3,20-dione bis(ethylene ketal), 2a-methyl-16ucarboxy-4-pregnene-3,l1,20 trione 3,20 bis(ethylene EXAMPLE 6A 11/i'-hydro'xy-16a-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VI) A solution of 9.7 g. of l6a-carbomethoxy-4-pregnene- 3,11,20-trione 3,20-bis(ethylene ketal) (V) in benzene was added at 0 C. to a stirred suspension of 12.0 g. of lithium aluminum hydride in ml. of ether and 150 ml. benzene. The mixture was heated under reflux for a period of about 4 hours and then cooled in an ice-water bath. The excess lithium aluminum hydride was decomposed by the addition of ethyl acetate and then water. The reaction mixture was then filtered and the organic layer was separated, washed with water and the solvent was removed by evaporation. The crude residue thus obtained was crystallized from ethyl acetate:Skellysolve B hexanes to give 2.4 g. of 1lfi-hydroxy-16a-hydroxymethyl-4-pregnene-3,20- dione bis(ethylene ketal) (VI) melting at 195205 C. A second crop of crystals from the mother liquors gave an additional 0.3 g. Recrystallization from acetonezSkellysolve B hexanes gave 1lfl-hydroxy-l6a-hydroxymethyl-4- 3,20-dione bis(ethylene ketal melting at 209-211 C. Chromatography of the mother liquors on Florisil synthetic magnesium silicate and elution with 20% acetonefikellysolve B hexanes gave an additional 0.79 g. of 1lfl-hydroxy-16ot-hydroxymethyl-4-pregnene-3,20 dione bis(ethylene ketal) melting at 195-205 C. The infrared spectrum supported the assigned structure.

Analysis.--Calcd. for C H O C, 69.61; H, 8.99. Found: C, 69.61; H, 9.61.

In the same manner, following the procedure of Example 6A but substituting other 16a-carbomethoxy-4- pregnene 3,20-bis(ethylene ketals), represented by Formula V, i.e., those listed in the fourth paragraph of Example 5A, for 16-carbomethoxy-4-pregene-3,11,20-trione 3,2()--bis(ethylene ketal) is productive of the corresponding 16a-hydroxymethyl-4-pregnene-3,ZO-dione bis(ethylene ketal) represented by Formula VI, i.e., 6u-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal), 20tmethyl 1lp-hydroxy-lot-tydroxymethyl 4 pregnene- 3,20-dione bis(ethylene ketal), 2a-methyl-l6a-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal), 6amethyl 11,8 hydroxy 1Get-11ydroxymethyl-4-pregnene- 3,20-dione bis(ethylene ketal), and 6a-methyl-16a-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal), respectively.

EXAMPLE 6A 1 1 5-12 ydroxy-l 6 cc-hyrlroxym ethyl -4-pregrzene-3 ,ZO-di one bis(ethylene ketal) (VI) A mixture of 5.08 g. of l6a-carboxy-4-pregnene- 3,11,20-trione 3,20-bis(ethylene ketal) and 3.5 g. of lithium aluminum hydride in 350 ml. of tetrahydrofuran was refluxed for a period of about 3 hours. The bisketal was introduced into the reatcion mixture employing the Soxhlet technique. The reaction mixture was cooled and then excess lithium aluminum hydride was decomposed by the addition of ethyl acetate and then water followed by filtration to remove the inorganic salts. The organic layer was separated, washed with water and evaporated in vacuo to remove the solvent. The residue thus obtained was crystallized from acetonezmethanol to give 3.9 g. of 11,8 hydroxy l6ot-hydroxymethyl-4-pregnene-3,20- dione bis (ethylene ketal) (VI).

In the same manner, following the procedure of Example 6A' but substituting other l6ot-carboxy-4-pregnene 3,20bis(ethylene ketals), represented by Formula V, i.e., those listed in the third paragraph of Example 5A for 16- carbornethoxy-4-pregnene 3,11,20-trione 3,20-bis(ethylene ketal) is productive of the corresponding 16a-hydroxymethyl-4-pregnene-3,ZO-dione bis(ethylene ketal) represented by Formula VI, i.e., l6a-hydroxymethyl-4- pregnene-3,20-dione bis(ethylene ketal), Za-methyl-llflhydroxy-l6a-hydroxymethyl-4-pregnene 3,20-dione bis (ethylene ketal), Ztx-methyl-loa-hydroxymethyl-4pregnene-3,20-dione bis(ethylene ketal), 6a-methy1-11p3-hydroxy 160a hydroxymethyl 4-pregnene-3,20-dione bis (ethylene ketal), and Get-methyl-16u-hydroxymethyl-4- pregnene-3,20-dione bis(ethylene ketal), respectively.

EXAMPLE 7A 1 Jfi-hydroxy-I 6 e-acetoxym ethyl-4 -pregnene-3,20-dine bis(ethylene ketal) A solution of 1.0 g. of 1lB-hydroxy-lda-liydroxymethyl- 4-pregnene-4,20-dione bis(ethylene ketal) (VI) in ml.

of acetic anhydride and 5 ml. of pyridine is allowed to stand at room temperature until the acylation is complete. The reaction mixture is then poured into ml. of icewater and the resutling aqueous mixture is extracted with three 25 ml. portions of methylene chloride. The extracts are combined, Washed with water, dried over sodium sulfide and evaporated in vacuo to remove the solvent. The residue thus obtained is recrystallized from acetonezSkellysolve B hexanes to give l1/3-hydroxy-16a-acetoxymethyl- 4-pregnene 3,20-dione bis(ethylene ketal).

In the same manner following the procedure of Example 7A but substituting as starting material other hydroxy compounds represented by Formula VI, and prepared in Example 6A, above, i.e., 2ot-methyl-11;3-hydroxy- 16cc hydroxymethyl-4-pregnene-3,20-dione bis (ethylene ketal) or 6a-methy1-1le-hydroxy-l6a-hydroxymethyl-4- pregnene-3,20-dione bis(ethylene ketal) for llfi-hydroxy- 16a hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) is productive of 2a-methy1-1lp-hydroxy-le-acetoxymethyl-4-pregnene-3,20-dione bis (ethylene ketal) and 6a methyl 1IB-hydroxy-16a-acetoxymethyl-4-pregnene- 3,20-dione bis(ethylene ketal), respectively.

EXAMPLE 8A 16ot-aceioxymethyl-4-pregnene-3,11,20-trione 3,20-bis (ethylene ketal) A mixture of 300 mg. of 11fi-hydroxy-16aacetoxy- 1 methyl-4-pregnene-3,20-dione bis(ethylene ketal) in 5 ml. of pyridine is added to a suspension of chromium trioxide: pyridine complex (prepared from 300 mg. of chromium trioxide and 5 ml. of pyridine). The reaction mixture is allowed to stand at room temperature for a period of about 18 to 24 hours. Water and benzene:ether (1:1) is then added and the mixture is stirred thoroughly and then filtered through Supercel diatomaceous earth. The organic layer is separated, washed with Water, dried over sodium sulfate and evaporated to remove the solvent, giving crude 16cc acetoxymethyl-4-pregnene-3,11,20-trione-3,20- bis(ethylene ketal). The crude product is recrystallized from acetonezSkellysolve B hexanes to give 16e-acetoxymethyl-4-pregnene 3,11,20 trione 3,20 bis (ethylene ketal), a crystalline solid. Alternatively, if desired, the residue may be purified by chromatography.

In the same manner following the procedure of Example 8A, but substituting as starting material Zea-methyl- 11fi-hydroxy-16a-acetoxymethyl-4-pregnene-3 ,ZO-dione bis (ethylene ketal) or 6a-methy l-l1/3-hydroxy-16e-acetoxymethyl-4-pregnene-3,20 'dione 'bis(ethylene ketal) prepared in Example 7A above, for llfl-hydroxy-l 6-2.CtOXY' methyl-4-pregnene-3,ZO-dione bis(ethylene ketal) is productive of Za-methyl-l6tx-acetoxymethyl-4-pregnene-3,I l, ZO-trione 3,20-bis(ethylene ketal) and 6a-methyl 16w acetoxymethy-4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal), respectively.

EXAMPLE 9A J6a-hydroxymethyl-4-pregn'en'e-3,l1,20-tri0ne 3,20-bis (ethylene ketal) (Vla) To 1.0 g. of 16wacetoxymethyl-4-pregnene 3,11,20- trione 3,20-bis(ethylene ketal) in 15 ml. of methanol is added 5 ml. of a 25 percent solution of sodium hydroxide in aqueous methanol. The reaction mixture is stirred in a nitrogen atmosphere and then allowed to stand overnight at room temperature. The reaction mixture is then diluted with 100 ml. of water, neutralized with dilute acetic acid and extracted three times with methylene chloride. The

In the same manner following the procedure of Example 9A, but substituting as starting material Zea-methyl- 16u-acetoxy-methyl-4-pregnene-3,11,20 trione 3,20 bis (ethylene ketal) or 6a-methyl-16a-acetoxymethyl-4-pregnene-3,11,20-t-rione 3,20-bis(ethylene ketal) prepared in Example 8A, above, is productive of Zoe-InCthYI-lfia-I'IY- droxymethyl-4-pregnene-3,11,20-trione 3,20 bis(ethylene ketal) (V121) and 6tt-methyl-16a-hydroxymethyl-4-pregnene-3,11,20-trione 3,20-bis (ethylene ketal) (VIa), respectively.

EXAMPLE 10A 1 lflv-hydroxy-I 6 ot-hydroxymethtyl-4-pregnenie-3,20-dione (Vlb) To a solution of 300 mg. ll/3-hydroxy-16ot-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal) (VI) in acetone containing 10% by volume of water was added 1 ml. of 25 percent sulfuric acid. The mixture was boiled for a period of about 10 minutes and then allowed to stand at room temperature to complete the hydrolysis. At the end of the reaction period excess sodium bicarbonate solution was added and the acetone was removed in vacuo at room temperature until crystallization commenced. An additional 50 ml. of water was added, and crystallization was allowed to proceed at C. The crystalline material was then collected by filtration and dried in vacuo to give 150 mg. of 1lfi-hydroxy-l6u-hydroxymethyl-4-pregnene-3,20- dione melting at 234-238 C. Recrystallization from acetonezSkellysolve B hexanes gave 1lfi-hydroxy-16ot-hydroxymethyl-4-pregnene 3,20 dione melting at 244- 246 C.,

ELOH max.

The infrared spectrum supported the assigned structure. Optical rotatory dispersion analysis showed the 17,8-c0nfiguration.

Analysis.Calcd. for C H O4 Found: C, 73.24; H, 9.35.

In the same manner following the procedure of Example A but substituting as starting material other 3,20- bis(ethylene ketals) represented by Formulae VI and VIa and prepared in Examples 6A and 9A, i.e., 16at-hydroxymethyl-4-pregnene-3,20-dione bis(ethylene ketal), 16a-hydroxymethyl-4-pregnene-3,11,20-trione 3,20 bis(ethylene ketal), Za-methyl-l1p-hydroxy-16ot hydroxymethyl 4- pregnene-3,20dione bis(ethylene ketal), 2a-methyl-l6ahydroxymethyl-4-pregnene-3,20-dione bis (ethylene ketal) ZOc-methyl-l6a-hydroxymethyl-4-pregnene-3,11,20 trione 3,20-bis(ethylene ketal), 6u-methyl-1lfi-hydroxy-l6a-hydroXymethyl-4-pregnene-3,20 dione bis(ethylene ketal), 6ot-methyl-16a-hydroxymethyl-4-pregnene-3,20 dione bis (ethylene ketal) and 6ot-methyl-l6oc-hydroxymethyl 4- pregnene-3,11,20-trione 3,20-bis(ethylene ketal) for 11phydroxy-16a-hydroxymethy l-4-pregnene-3,20 dione bis (ethylene ketal) is productive of other compounds represented by Formula VIb, i.e., 16a-hydroxymethyl-4-pregnene-3,20-dione, l6ct-hydroxymethyl-4-pregnene 3,11,20- trione, Za-methyl-Ile-hydroxy-16a-hydroxymethyl-4-pregnene-3,20-dione, Za-methyl-l6a-hydroxymethyl-4 pregnene-3,20-dione, Zu-methyl-I6(z-hydroxyrnethyl-4 pregnone-3,11,20-trione, 6oc-I1l6thYl-l lfl-lhydroxy-la-hydroxymethyl-4-pregnene-3,20-dione, 6a-methyl-16a hydroxymethyl-4-pregnene-3,20-dione and 6ot-methyl-l6a-hydroxymethyl-4pregnene-3,l1,20-trione, respectively.

EXAMPLE 11A 1 dot-fluoromethyl-l 1 fi-hya'roxyl-pregn ens-3,20-di0ne bis(ethylene ketal (VIII) A solution of 1.0 g. of 1lfi-hydroxy-16m-hydroxymethyl- 4-pregnene-3,20-dione bis(ethylene ketal) (VI) and 1.0 g. of p toluenesulfonyl chloride in pyridine is allowed to stand for a period of about 18 to 24 hours at room temperature. The reaction mixture is then poured into ice water and extracted with methylene chloride. The combined methylene chloride extracts are washed consecutively with sodium bicarbonate solution and water and dried over sodium sulfate. The methylene cholride is then removed by evaporation giving crude llfl-hydroxy-l6a-(p-toluenesulfonyloxymethyl)-4pregnene 3,20 dione bis(ethylene ketal) (VII). The crude 1lfi-hydroxy-16ot-(p-t0luenesulfonyloxymethyl)-4-pregnene 3,20 dione bis(ethylene ketal) is dissolved in about 25 ml. of redistilled diethylene glycol and heated with 2.4 g. of anhydrous potassium fluoride at 200-210" C. for about 1 hour under an atmosphere of nitrogen. The reaction mixture is then cooled, poured int-o water and extracted with ethyl acetate. The extracts are combined, washed with water, and dried over sodium sulfate. The solvent is then removed by evaporation giving a crude residue containing 1lfi-hydroxy-16a-fluoromethyl- 4-pregnene-3,20-dione bis(ethylene ketal). The crude residue is dissolved in methylene chloride, chromatographed on g. of Florisil synthetic magnesium silicate and eluted with increasing proportions of acetone in Skellysolve B hexanes. The solvent is evaporated from each of the fractions and those containing crystalline material are combined and recrystallized from acetonezSkellysolve B hexanes to give 1lp-hydroxy-16w fluoromethyl-4-pregnene-3,20 dione bis(ethylene ketal) (VIII) melting at l83-185 C. The infrared spectrum is in agreement with the structure.

Analysis.--Calcd. for C H FO C, 69.34; H, 8.67; F, 4.22. Found: C, 69.61; H, 9.03; F, 3.74.

In the same manner, following the procedure of Example llA but substituting other 16a-hydroxymethyl-4- pregnene-3,20-dione bis(ethylene ketals), represented by Formula VI, i.e., those listed in the second paragraph of Exampl 6A for 1LB-hydroxy-16e-hyd1'oxymethyl-4-p-regnene-3,20-dione bis(ethylene ketal) is productive of the corresponding 16a-(p-toluenesulfonyloxymethyl)-4-pre nene-3,20-dione bis(ethylene ketal) represented by Formula VII, i.e., 16a-(p-toluenesulfonyloxymethyl)-4-pregnene-3,20-dione bis(ethylene ketal), 2ot-methyl-11 3-hydroxy a (p-toluenesulfonyloxymethyl)-4-pregnene- 3,20-dione bis (ethylene ketal), 2a-methyl-l6a-(p-toluene sulfonyloxymethyl)-4-pregnene 3,20 dione bis(ethylene ketal), 6a-methyl-l l fi-hydroxy- 1 6w p-toluenesulfonyloxymethyl)-4-pregnene-3,20-dione bis(ethylene ketal) and 6a-methyl-16a-(p-toluenesulfonyloxymethyl) 4 pregnene-3,20-dione bis(ethylene ketal), respectively. The 160c- (p-toluenesulfonyloxymethyl) compounds thus produced are converted to the corresponding l6a-fiuorornet-hyl compounds (VIII) with anhydrous potassium fluoride in the same manner as in Example 11A to give l6oc-fill010- methyl-4-pregnene 3,20 -=dione bis(ethylene ketal), 2amethyl-1lp-hydroxy-16a-fluoromethyl 4 pregnene-3,20- dione bis(ethylene ketal), 2a-methyl-16oz-fluoromethyl-4- pregnene-3,20-dione bis(ethylene ketal), 6a-methyl-11flhydroxy 16oz fluoromethyl 4 pregnene-3,20-dione bis- (ethylene ketal) and 6a-methyl-l6a-fluoromethyl-4-pregnene-3,20-dione bis(ethylene ketal), respectively.

In the same manner, following the procedure of Example llA but substituting as the starting steroid the ll-keto compounds represented by Formula VIa prepared in Example 9A and the paragraph following Example 9A is productive of the corresponding lda-p-toluenesulfonyloxymethyl derivatives (VII) which are then converted with potassium fluoride to the corresponding 11- keto-l6a-fiuoromethyl compounds (VIII), i.e., 16a-fil1010- methyl-4-pregnene-3,1l,20-trione 3,20 bis(ethylene ketal), Zea-methyl 16a fluoromethyl-4-pregnene-3,l1,20-trione 3,20-bis(ethylene ketal) and 6u-methyl-l6a-fluoromethyl- 4-pregnene-3,11,20-trione 3,20-bis(ethylene ketal), respectively.

EXAMPLE 12A I1fi-hydroxy-I6ot-flu0r0methyl-4-pregnene- 3,20-dione (IX) To a solution of 300 mg. llfi-hydroxy-l6a-fluoromethly-4-pregnene-3,20-dione bis(ethylene ketal) (VIII) in acetone containing 10% by volume of Water is added 1.0 ml. of 25 percent sulfuric acid; the solution is boiled for about 10 minutes and then allowed to stand at room temperature until hydrolysis is complete. At the end of the reaction excess sodium bicarbonate solution is added and the acetone is removed in vacuo at room temperature until crystallization commences. An additional 50 ml. of water is then added and the crystallization is allowed to proceed at C. The solid material thus obtained is collected by filtration, Washed with water and dried in vacuo to give 1LB-hydroxy-l6a-fluoromethyl-4-pregnene- 3,20-dione, a crystalline solid. The product can be further purified by recrystallization from acetonezSkellysolve B hexanes.

In the same manner following the procedure of EX- ample 12A, but substituting as starting material other 161- fluoromethyl-4-pregnene-3,ZO-dione bis(ethylene ketals) represented by Formula VIII, i.e., the 16a-fluoromethyl compounds prepared and listed in the second and thrd paragraphs of Example 11A for l1B-hydroxy-l6a-fluoromethyl-4-pregnene-3,20'dione bis(ethylene ketal) is productive of the corresponding hydrolyzed compound (IX), i.e., 16ix-fluoromethyl-4-pregnene-3,20-dione, Za-methylllfl-hydroxy-l6oi -fluoromethyl-4 pregnene3,20-dione, 2arnethyl 16a fluoromethyl-4-pregnene-3,ZO-dione, 60cmethyl 11,8 hyd-roxy-l6a-fiuoromethyl-4-pregnene-3,20- dione, 6u-methyl-l6ix-fluoromethyl-4-pregnene-3,20-dione, l6a-fluoromethyl-4-prcgnene 3,11,20 trione, Zea-methyl- 16a fluoromethyl 4 pregnene 3,11,20 trione and 60amethyl'lfiu-fluoromethyl 4 pregame-3,11,20-trione, respectively.

EXAMPLE 13A I6a-flzt0r0methyl-4-pregnene-3,1[JO-trione (IX) A mixture of 280 mg. of llfi-hydroxy-l6ct-fluoro methyl-4-pregnene-3,ZO-dione bis(ethylene ketal) (VIII) and 5 ml. of pyridine is added to a suspension of chromium trioxide: pyridine complex (prepared from 300 mg. of chromium trioxide and 5 ml. of pyridine). The reaction mixture is allowed to stand at room temperature until the oxidation is completed. Water and benzene:ether (1:1) are then added. The mixture is stirred thoroughly and filtered through Supercel diatomaceous earth. The organic layer is separated, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained, containing l6u-fiuoromethyl-4- pregnene-3,ll,20-trione bis(ethylene ketal) is dissovled in 50 ml. of acetone and 5 m1. of water and hydrolyzed by standing at room temperature for a period of about 30 hours with 0.5 ml. of 25% sulfuric acid. At the end of the reaction excess sodium bicarbonate solution is added and the acetone is removed in vacuo at room temperature until crystallization commences. An additional 100 ml. of water is then added and the crystallization is allowed to proceed at 0 C. The crystalline solid is collected by filtration, Washed with water and dried to give crude 16afluoromethyl-4-pregnene-3,l1,20-trione. The crude product thus obtained is recrystallized twice from acetone:Skellysolve B hexanes to give l6a-fiuoromethyl-4- pregnene-3,Ill,20-trione (IX) melting at 223-226 C.

In the same manner following the oxidation procedure of Example 13A, but substituting as starting material 200- methyl-llfi-hydroxy-l6lx-fluoromethyl 4 pregame-3,20- dione bis(ethylene ketal) (VIII) or fia-methyl-llfi-hydroxy 16a fluoromethyl 4 pregnene-3,20-dione bis- (ethylene ketal) (VIII) (prepared in Example 11A) for llfi-hydroxy-l6oi-fluoromethyl-4-pregnene 3,20 dione bis(ethylene ketal) is productive of 2a-methyl-l6a-fiuoromethyl 4 pregnene 3,11,20 trione 3,20-bis(ethylene ketal) and 6a methyl 16oz fiuoromethyl 4 pregnene- 3,11,20 trione 3,20 --bis(ethylene ketal), respectively, which when subjected to hydrolysis according to the procedure of Example 13A is productive of 2a-methyl-l6otfluoromethyl-4-pregnene-3,11,20-trione X) and 60a- 36 methyl-1(Six-fluoromethyl-4-pregnene-3,l1,20-trione (IX), respectively.

EXAMPLE 14A A mixture of 20.0 g. of 3e-acetoxy-lG-pregnene-l1,20- dione (A-I), 30.0 g. of potassium cyanide, 1 liter of methanol and 200 ml. of dioxane was heated to boiling under reflux for a period of 3 hours. At the end of the reilux period the reaction mixture was cooled, water was added and the organic material was extracted with methylene chloride. The combined extracts were washed with water, dried over sodium sulfate and evaporated to remove the solvent. The crystalline residue thus obtained was recrystallized from acetonezSkellysolve B hexanes to give 95 g. of 3a-hydroxy-l6e-cyano 5;3-pregnane-11,20- d one melting at 222-226 C. Further recrystallization from acetonezSkellysolve B hexanes gave 3a-hydroxyl6a-cyano 5,8 pregnane-1l,20-dione (A-II) melting at 238240 C.; the infrared spectrum agreed with the assigned structure and optical rotatory dispersion analysis indicated the l7B-configuration.

Alzalysis.Calcd. for C H O Nr C, 73.91; H, 8.74; N, 3.92. Found: C, 74.34; H, 9.04; N, 4.11.

EXAMPLE 15A A mixture of 5.5 g. of 3a-hydroxy-lGa-cyano-Sfipregmane-11,20-dione (A--II), 25 ml. of ethylene glycol, 250 mg. of p-toluenesulfonie acid monohydrate and 500 ml. of benzene was heated to reflux for a period of 6 hours. Water was removed during the reflux period by use of a conventional water separator. The reaction mixture was then cooled in an iceavatcr bath and saturated. aqueous sodium bicarbonate solution was added. The benzene layer was separated and the aqueous layer was extracted with additional benzene. The combined benzene extracts were washed with water until neutral, dried over sodium sulfate and evaporated to remove the solvent. The oil thus obtained was dissolved in methylene chloride and chromatographed on 300 g. of Florisil synthetic magnesium silicate which had been pre-treated with Skellysolve B hexanes. The column was eluted with increasing proportions of acetone in Skellysolve B hexanes. The solvent was removed from the eluates by evaporation. Crystalline material was obtained from the fractions eluted with 20% acetonezSlcellysolve B hexanes. These fractions were combined and recrystallized from ether to give 3.25 g. of 3ahydroxy 16cc cyano 5B pregnane 11,20-dione 20- ethylene ketal melting at 164-l70 C. A second crop of crystals was obtained from the mother liquors giving an additional 0.54 g. of 3a-hydroxy-1Ga-cyano-SB- regnane- 11,20-dione 20-ethylene ketal. Further recrystallization from ether gave 3a-hydroxy-l6a-cyano-5B-pregnane-l1, 20-dione 20-ethylene ketal (A-III) melting at 168-170 C. The infrared spectrum confirmed the structure.

Analysis.Calcd. for C H O N: C, 71.79; H, 8.79; N, 3.49. Found: C, 71.12; H, 8.67; N, 3.68.

EXAMPLE 16A 3ut-hydn0xy-16a-carbometh0xy-5fl-pregnane-11,20- dione ZO-ethylene ketal (A-I V) A solution of 2.85 g. of 3a-hydroxy-l6oc-cyano-5 8- pregnane-l 1,20-dione 20-ethylene ketal (A-III) and 5.0 g. of potassium hydroxide in ml. of ethylene glycol and 20 ml. of water was heated to boiling under reflux in a nitrogen atmosphere for a period of 24 hours. The solution was then cooled, diluted with about 250 ml. of water and extracted twice with methylene chloride. The aqueous layer was then carefully acidified to about pH 4, first with sodium dihydrcgen phosphate and then with ice cold dilute hydrochloric acid, and rapidly extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water until neutral, dried over sodium sulfate and evaporated in vacuo to remove the solvent. The residue thus obtained was dissolved in 250 ml. of methanol and 250 ml. of methylene chloride and esteritied with excess ethereal diazomethane at room temperature for a period of 3 hours. The solvent was then removed by evaporation in vacuo. The residual oil thus obtained was dissolved in acetonezSkellysolve B hexanes and crystallized to give 2.21 g. of 3a-hydroxy-16a-carbomethoxy 5e pregnane 11,20 dione 20 ethylene ketal melting at 221223 C. Further recrystallization gave 30: hydroxy 16a carbomethoxy 56 pregnanc- 11,20-dione ZO-ethylene ketal (A-IV) melting at 222- 223 C. The infrared spectrum supported the structure.

Analysis.Calcd. for C H O C, 69.09; H, 8.81. Found: C, 69.29; H, 8.89.

EXAMPLE 17A 16a-carbomethoxy-Sfi-pregnanc-S,11,20-trione 3,20- bis(elhylene ketal) (A-V) A solution of 2.05 g. of 3ot-hydroxy-16ot-carbomethoxy 5,6 pregnane 11,20 dione 20 ethylene ketal (AIV) in 200 ml. of acetone was oxidized for 5-10 minutes at C. with 1.85 ml. of standard chromium trioxide:sulfuric acid reagent (prepared by dissolving 26.72 g. of chromium trioxide in 25 ml. of concentrated sulfuric acid and diluting with water to 100 ml.). Saturated aqueous sodium bicarbonate solution was then added to the reaction mixture followed by filtration through Supercel diatomaceous earth. The filtrate was extracted with methylene chloride and the combined extracts were Washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residual oil thus obtained was dissolved in acetonezSkellysolve B cxanes and crystallized to give 1.73 g. of 16ot-carbome thoxy-e-prcgnane-3,11,20-trione ZO-ethylene ketal melting at 154 to 156 C.

A mixture of 1.68 g. of 16a-carbomethoxy-5 8-pregmane-3,11,20-trione 20-ethylene ketal, 10 ml. of ethylene glycol, 150 mg. of p-toluenesulfonic acid monohydrate and 200 ml. of benzene was heated to reflux incorporating a water separator for a period of 16 hours. The reaction mixture was then cooled and sodium bicarbonate solution was added. The organic layer was separated from the aqueous layer, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue, thus obtained, was crystallized from acetonezSkellysolve B hexanes to give 1.74 g. of 16a-carbomethoxy 56 prcgnane 3,11,20 trione 3,20-bis (ethylene ketal) (A-V) melting at 200-225 C. The infrared spectrum supported the assigned structure.

Analysis.Calcd. for C H O C, 68.04; H, 8.46. Found: C, 67.74; H, 8.48.

EXAMPLE 18A 1 I/B-hydroxy-l 6 a-hydrOJtyInQthyZ-S B-pregnane- 3,20-a'i0ne bis(ethyl ne ketal) (A-VI) A solution of 1.6 g. of 16a-carbornethoxy-Sfi-pregnane- 3,11,20-trione 3,20-bis(ethylene ketal) in 50 ml. of henzene was added dropwise to a stirred suspension of 2.0 g. of lithium aluminum hydride in 30 ml. of diethyl ether and 20 ml. of benzene keeping the temperature at 0 C. or below. The mixture was then heated under reflux for a period of about 4 hours. The reaction mixture was cooled and the excess hydride was decomposed with ethyl acetate followed by about 5 ml. of water. The organic layer was then filtered with the aid of Supercel diatoma ceous earth. The filtrate was washed with water, dried over sodium sulfate and evaporated to remove the solvent giving 1.605 g. of crude product which when crystallized from acetonezSkellysolve B hexanes gave 1.18 g. of 11 3- hydroxy 16a hydroxymethyl 5e pregnane 3,20- dione bis(ethylene ketal) melting at 196-203 C. Two

38 recrystallizations from acetone:Skellysolve B hexanes gave 11,8 hydroxy-l6a-hydrQXymethyI-Sfi-pregname-3,20- dione bis(ethylene ketal) (AVI) melting at 204-205 C. The infrared spectrum supported the assigned structure. Analysis.-Calcd. for (3261 14206: C, 69.30; H, 9.40. Found: C, 69.53; H, 9.41.

EXAMPLE 19A JIfi-hydroxy-I 6zz-fluoromethyl-4-pregnene-i20- dione bis(ethylene ketal) (A-VIII) A solution of 0.82 g. of 115-hydroxy-16a-hydroxymethyl-Sfl-pregnane-B,20-dione bis(ethylene ketal) (A- VI) and 0.82 g. of p-toluenesulfonyl chloride in 16 ml. of pyridine was allowed to stand for a period of 18 hours at room temperature. The reaction mixture was then poured into ice water and extracted with methylene chloride. The combined methylene chloride extracts were washed consecutively with sodium bicarbonate solution and water, and dried over sodium sulfate. The methylene chloride was then removed by evaporation giving 1.418 g. of crude 1le-hydroxy-l6a-(p-toluenesulfonyloxymethyl)-5,B-pregnane-3,20-dione bis(ethylene ketal) (AVH).

The crude lle-hydroxy 16oz. (p-toluenesulfonyloxymethyl)-5 9-pregnane-3,20-dione bis(ethylene ketal) was dissolved in 25 ml. of redistilled diethylene glycol and heated with 2.0 g. of anhydrous potassium fluoride at C. for a period of 18 hours under an atmosphere of nitrogen. The reaction mixture was then cooled, poured into water and extracted with ethyl acetate. The extracts were combined, washed with water, and dried over sodium sulfate. The solvent was then removed by evaporation giving 814 mg. of residual oil containing crude 1l/8-hydroxy-16a-fluOrOmethyl-Sfi-pregnane-3,20-dione bis(ethylene ketal). The residual oil was dissolved in Skellysolve B hexane, chromatographed on 100 g. of Florisil synthetic magnesium silicate and eluted with increasing proportions of acetone in Skellysolve B hexanes. The solvent was removed from the fractions and those fractions which were eluted with 5% acetone:Skellysolve B hexanes contained 404 mg. of crystalline material which was combined and recrystallized from acetonetSkellysolve B hexanes to give 310 mg. of 1lfi-hydroxy-l6a-fiuoromethyl- 5fl-pregnane-3,20-dione bis(ethylene ketal) melting at 120 C. Two additional recrystallizations from acetone:Skellysolve B hexanes gave 11fl-hYClfOXY-16a-flll0l0- methyl-SB-pregnane-3,20-dione bis(ethylene ketal) (A- VIII) melting at -127 C. The infrared spectrum supported the assigned structure.

Analysis.Calcd. for C H FO C, 69.04; H, 9.07; F, 4.20. Found: C, 68.90; H, 9.46; F, 3.99.

EXAMPLE 20A I6a-flu0romethyl-5B-pregnans-3,11,20-tri0ne (A-IX) A solution of 283 mg. of 1lfl-hydroxy-l6a-fiuoromethyl-5fi-pregnane-3,20-dione bis(ethylene ketal) (A-VIII) in 5 ml. of pyridine was added to a suspension of chromium trioxide1pyridine complex (prepared from 300 mg. of chromium trioxide and 5 ml. of pyridine). The reaction mixture was allowed to stand at room temperature for a period of 18 hours. Water and benzene:ether (1:1) was then added and the mixture was stirred thoroughly, and filtered through Supercel diatomaceous earth. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained, containing 16ot-fluoromethyl-5flpregnane-3,11,20-trione bis(ethylene ketal) was dissolved in 50 ml. of acetone and 5 ml. of water and hydrolyzed by standing at room temperature for a period of 30 hours with 0.5 ml. of 25% sulfuric acid. At the end of the reaction period excess sodium bicarbonate solution was added and the acetone was removed in vacuo at room temperature until crystallization commenced. An additional 100 m1. of water was then added and the crystallization was allowed to proceed at C. The crystalline solid was collected by filtration, washed with water and dried to give 200 mg. of crude product which was recrystallized from acetonezSkellysolve B hexanes to give 130 mg. of 16a fluoromethyl a pregnane 3,11,20 trione melting at 162 to 165 C. A final crystallization from the same solvent gave 16a-fiuOrOmethyI-SB-pregnane-3,11,20- trione (A-IX) melting at 164-166 C. The infrared spectrum supported the assigned structure.

Analysis.Calcd. for C H FO C, 72.90; H, 8.56; F, 5.25. Found: c, 72.80; H, 3.92; F, 5.26.

EXAMPLE 21A 16u-flu0r0methyl4-pregnene-3,11,20-tri0ne (IX a) A solution of 1.05 g. of 16u-fiuoromethyI-Sfl-pregnane- 3,11,20-trione in 35 ml. of t-butanol and 2 ml. of dioxane was stirred in the dark at room temperature with 0.3 ml. of concentrated hydrochloric acid, 1.5 ml. of water and 0.35 ml. of t-hutyl hypochlorite for a period of 24 hours. The reaction mixture was then diluted with water and extracted with methylene chloride. The extracts were combined, washed with sodium bicarbonate solution, water, and dried over sodium sulfate. The solvent was removed in vacuo giving 1,283 g. of crude 4-ch1oro-16ct-flu0romethyl-5fi-pregnane-3,l1,20-trione. The crude 4-chloro compound was dissolved in 35 ml. dimethylformamide and heated at 5060 C. in a nitrogen atmosphere with 1.38 g. of semicarbazide hydrochloride, 1.03 g. of sodium acetate and 7 ml. of water. After 2 hours, 3.45 ml. of pyruvic acid and 3.45 ml. of water were added and the solution was maintained at the same temperature for an additional 2.5 hours. The reaction mixture was then cooled and benzene and sodium bicarbonate solution were added. The organic layer was separated, washed with water and dried over sodium sulfate. The solvent was removed by evaporation in vacuo giving 1.28 g. of residual oil which was dissolved in methylene chloride and chro matographed on 100 g. Florisil synthetic magnesium silicate which had been pre-treated with Skellysolve B hexanes. The column was eluted with increasing proportions of acetone in Skellysolve B hexanes. Crystalline material was obtained from the fractions eluted with 10-15% acetone:Skellysolve B hexanes. The crystalline material was combined and crystallized from acetonezSkellysolve B hexanes to give 0.45 g. of 16a-fluoromethyll-pregnene- 3,11,20-trione melting at 203208 C. Two further recrystallizations from acetone:Skellysolve B hexanes gave 16wfluoromethyl-4-pregnene-13,11,20-trione (IXa) melting at 223226 C.,

max.

238 my, (1M 15,400

EXAMPLE 22A 3fl-hydroxy-I6a-cyan0-5-pregnen-20-0ne -ethylene ketal (AII) A mixture of 68.0 g. of 3p-hydroxy-16a-cyano5-pregnen-20-one (A'-I), 250 ml. of ethylene glycol, 2 liters of benzene and 2.0 g. of p-toluenesulfonic acid monohydrate was heated under reflux for a period of 5 hours. Water was removed during the reflux period by incorporating a water separator into the reflux return. The reaction mixture was cooled and benzene and sodium bicarbonate solution were added. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residue thus obtained was crystallized from acetonezSkellysolve B hexanes to give 42.3 g. of 3fi-hydroxy-16a-cyano-5-pregnen-20-one ZO-ethylene ketal (AII) melting at 189-192" C.

40 EXAMPLE 23A 3,8-hydroxy-16a-carb0xy-5-pregnen-20-one 20-ethylene ketal (A'-III) A mixture of 42.0 g. of 3,8-hydroxy-16a-cyano-5-pregnen-20-one ZO-ethylene ketal, 1 liter of ethylene glycol, 250 ml. of water and 75.0 g. of potassium hydroxide were refluxed with stirring under an atmosphere of nitrogen for a period of 20 hours. The solution was cooled to room temperature and filtered. The aqueous alkaline filtrate was cooled to 0 C. and acidified with ice-cold dilute hydrochloric acid to give 3/3-hydroxy-16a-carboxy-5-pregnen-20-one 20-ethylene ketal as a precipitate, which was collected by filtration, washed with water and dried to give 20.0 g. melting at 220-240 C. Crystallization from acetone:methanol gave 3B-hydroxy-16cz-carboxy-5-preg nen-20-one 20-ethylene ketal (AIII) melting at 245- 248" C. The infrared spectrum supported the assigned structure.

Analysis.-Calcd for C H O C, 71.35; H, 8.97. Found: C, 70.58; H, 9.60.

EXAMPLE 24A A mixture of 10.0 g. 3p-hydrexy-16a-carboxy-5-pregnen-ZO-one 20,-ethylene ketal (A'--III), ml. of henzene, 20 ml. of dihydropyran and 100 mg. of p-toluenesulfonic acid monohydrate was stirred for a period of 18 hours at room temperature. At the end of the reaction pe-- riod aqueous sodium bicarbonate solution was added and the organic layer was separated, washed with water, dried over sodium sulfate, and evaporated to remove the solvent. The residual oil thus obtained was dissolved in 200 ml. of benzene and 50 ml. of ether and this solution was added dropwise with stirring to a suspension of 10.0 g. of lithium aluminum hydride in 250 ml. of ether at 0-5 C. The mixture was then heated to boiling under reflux for a period of 4 hours. At the end of the reflux period the mixture was cooled and the excess lithium aluminum hydride was decomposed by the successive addition of ethyl acetate and water, followed by filtration to remove the inorganic salts. The filtrate was evaporated to dryness and the residue thus obtained was dissolved in 200 ml. of pyridine and allowed to stand for a period of 48 hours at room temperature with 10 g. of p-toluenesulfonyl chloride. Benzene and water were then added. The organic layer was separated, washed consecutively with ice-cold dilute sulfuric acid, water, aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo to remove the solvent.

The residual oil thus obtained was mixed with 50 ml. of redistilled, diethylene glycol and 10 g. of anhydrous potassium fluoride and heated for 1 hour at 205225 C. with stirring under an atmosphere of nitrogen. After cooling, 50 ml. of dioxane and 500 ml. of 25% sulfuric acid were added and the solution was allowed to stand over night at room temperature. The organic material was then extracted with methylene chloride and the combined extracts were washed with aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated to remove the solvent. The residual oil thus obtained, was dissolved in methylene chloride and chromatographed on 500 g. of Florisil synthetic magnesium silicate which had been pretreated wtih Skellysolve B hexanes. The column was eluted with increasing proportions of acetone in Skellysolve B hexanes. Crystalline material was obtained from the 20% acetone:Skellysolve B hexane eluates. These were combined and crystallized from acetone:Skellysolve B hexanes to give 0.535 g. of BB-hydroxy-l6a-fluoromethyl-5-pregnen-20-one melting at 174-177 C. Recrystallization from acetonezSkellysolve B hexanes gave 3B-hydroxy- 16o:-fiuoromethyl-S-pregnen-ZO-one (A'IV) melting at 182-184 C. The infrared spectrum agreed with the as- 

8. A COMPOUND OF THE FOLLOWING FORMULA: 